Analysis of novel cellular responses and serological markers in colorectal cancer patients

In recent years there have been significant advances in the treatment of cancer. This has been particularly aided by the discovery and exploitation of checkpoint inhibition; immunotherapy has the potential to induce sustained responses and increased survival in some patients. In solid tumours such as colorectal cancer (CRC), however, these therapies only benefit a small subgroup of patients. This is thought to be a result of poor tumour immunogenicity and low immune cell infiltration. In light of this, efforts are underway to identify new immunotherapeutic approaches to both alleviate tumour-mediated immunosuppression, and to increase anti-tumour immune responses. The Godkin/Gallimore research group has recently completed a clinical trial, “TroVax and Cyclophosphamide Treatment in Colorectal Cancer” (TaCTiCC), in which the ability of cyclophosphamide (CPM) and 5T4 cancer vaccine TroVax to induce immune responses in advanced metastatic CRC (mCRC) patients was assessed. Unexpectedly, these treatments were found to not only induce immune responses but were also associated with increased survival in a proportion of patients, therefore may represent new treatment options for mCRC patients. Given the rapid explosion in the number of available immunotherapies, it is vital that we understand which patients will benefit from treatment. This thesis investigates a panel of plasma proteins and serological/immunological markers to identify mCRC patients who responded to CPM and TroVax on the TaCTiCC trial; several potential biomarkers of response to both therapies have been identified. Plasma proteins were also assessed for their ability to identify earlier-stage and mCRC patients both from each other, and from healthy donors; there is a clear and significant difference in circulating plasma proteins between these groups. Finally, this thesis investigates T cell responses to 7 novel CRC tumour antigens recently identified within the Godkin/Gallimore group; responses to several antigens are reduced in CRC patients compared to healthy donors and may therefore represent useful immunotherapy targets. It is hoped that the findings described in this thesis will contribute to the improved identification of CRC, and to our understanding of factors associated with immunotherapy response. Moreover, the identification of novel CRC antigen targets may inform the development of improved immunotherapies